Rosuvastatin belongs to a class of drugs called statins, which act as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase. Statins are effective in reducing low-density lipoprotein (LDL) particles concentration in the blood stream and used in the treatment of hypercholesterolemia and hyperlipoproteinemia. Moreover, they are very useful in preventing coronary heart disease (CHD), which continues to be a major health problem in developed countries.
Rosuvastatin is used in the form of Rosuvastatin calcium, which is more desirable since it can be more efficiently formulated. This is important, because formulations need to meet certain pharmaceutical requirements and specifications. Rosuvastatin calcium can be easily formulated in the form of tablets, capsules, lozenges, powders, and other forms for oral administration.
Rosuvastatin calcium is chemically designated as (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid calcium salt (2:1). Rosuvastatin calcium is represented by the following structure of formula II:
(E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methylmethanesulfonamide is also known as (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methylsulfonylamino)pyrimidin-5-yl]-propenal and has the following structural formula (I). Said compound of formula (I) is a useful intermediate for the preparation of Rosuvastatin.

Various methods are already known for the preparation of (E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(3-oxoprop-1-enyl)pyrimidin-2-yl)-N-methylmethanesulfonamide or derivates thereof. Prior art processes for the preparation of compound of Formula (I) present the disadvantage of non-satisfactory yield of the product. Furthermore, the compound often comprises significant amounts of impurities.
WO-A-2006/100689 discloses a process for the preparation of the propenal intermediate, wherein the starting material N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, herein referred to as the carboxaldehyde intermediate, is subjected to a Wittig-type coupling reaction with a stabilized phosphorus species. The propenal intermediate is further prepared by reduction using DIBAL then oxidation using pyridine/CrO3.
However, this process requires the use of CrO3 in large excess, which is a known toxic, corrosive and carcinogenic reagent. Further, the addition and quenching of the DIBAL reagent must be carried out with extreme caution, strictly at low temperatures for safety reasons.
Moreover, this process requires the use of column chromatography for the isolation of the Witting-coupling product, which results in a process that is not cost effective for large-scale industrial production. The total reaction time of the process is more than 15 hours, wherein 6 hours out of said total reaction time are under reflux conditions, and additional time must be invested in the lengthy workup procedures of the last two steps.
WO-A-2008/072078 discloses a four-step process for the preparation of the propenal intermediate from the carboxaldehyde intermediate. This process requires a lengthy basic hydrolysis step to generate a mixed anhydride intermediate. This intermediate is then reduced to the corresponding alcohol intermediate, which is further oxidized to obtain the carboxaldehyde intermediate. The reaction step requires either cryogenic conditions using a highly reactive and hazardous LiAlH4 reagent or long reaction time and column purification using NaBH4.
Further, in the final oxidation step, MnO2 is added in large excess. The total reaction time is too long and the yield of said process is low. This process is not feasible for large scale production.
WO-A-2010/038124 discloses a two-step process for the preparation of the propenal intermediate, comprising a first step of a high-yielding Grignard reaction, which leads to a secondary alcohol intermediate, and a second step such as a chain extension process using a highly toxic and corrosive POCl3 reagent in molar excess. The target propenal intermediate is purified by recrystallization. The total reaction time of this process exceeds 36 hours and the overall yield is moderate.
Although each of the above patents represents an attempt to overcome the use of costly and hazardous material, there still exists a need for a cost-effective and safer process for large scale production which provides higher yield with higher purity.